chr11-95835367-A-G

Variant names:

• chr11-95835367-A-G
• rs116750638
• NM_016156.6:c.1855T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016156.6(MTMR2):​c.1855T>C​(p.Ser619Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,613,144 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S619C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (22 hom.)
• Consequence: MTMR2 NM_016156.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 1.28
• Publications: 4 publications found

Genes affected

MTMR2 (HGNC:7450): (myotubularin related protein 2) This gene is a member of the myotubularin family of phosphoinositide lipid phosphatases. The encoded protein possesses phosphatase activity towards phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate. Mutations in this gene are a cause of Charcot-Marie-Tooth disease type 4B, an autosomal recessive demyelinating neuropathy. Alternatively spliced transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

MTMR2 Gene-Disease associations (from GenCC):

• demyelinating hereditary motor and sensory neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 4B1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077272058).
• BP6: Variant 11-95835367-A-G is Benign according to our data. Variant chr11-95835367-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 234375.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00202 (308/152162) while in subpopulation SAS AF = 0.0133 (64/4828). AF 95% confidence interval is 0.0107. There are 2 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016156.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR2	NM_016156.6	MANE Select	c.1855T>C	p.Ser619Pro	missense	Exon 15 of 15	NP_057240.3
	MTMR2	NM_001440647.1		c.1771T>C	p.Ser591Pro	missense	Exon 14 of 14	NP_001427576.1
	MTMR2	NM_001440648.1		c.1762T>C	p.Ser588Pro	missense	Exon 14 of 14	NP_001427577.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR2	ENST00000346299.10	TSL:1 MANE Select	c.1855T>C	p.Ser619Pro	missense	Exon 15 of 15	ENSP00000345752.6
	MTMR2	ENST00000352297.11	TSL:1	c.1639T>C	p.Ser547Pro	missense	Exon 16 of 16	ENSP00000343737.7
	MTMR2	ENST00000393223.8	TSL:1	c.1639T>C	p.Ser547Pro	missense	Exon 16 of 16	ENSP00000376915.3

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152044 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00204

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00278 AC: 696 AN: 250592 AF XY: 0.00326

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000987

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00204

Gnomad NFE exome AF: 0.00234

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00213 AC: 3119 AN: 1460982 Hom.: 22 Cov.: 30 AF XY: 0.00251 AC XY: 1821 AN XY: 726788

African (AFR) AF: 0.000239 AC: 8 AN: 33448

American (AMR) AF: 0.00128 AC: 57 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00333 AC: 87 AN: 26100

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.00983 AC: 848 AN: 86236

European-Finnish (FIN) AF: 0.00208 AC: 111 AN: 53378

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5762

European-Non Finnish (NFE) AF: 0.00164 AC: 1826 AN: 1111426

Other (OTH) AF: 0.00242 AC: 146 AN: 60338

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152162 Hom.: 2 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74414

African (AFR) AF: 0.000385 AC: 16 AN: 41554

American (AMR) AF: 0.00203 AC: 31 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4828

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00240 AC: 163 AN: 67942

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00212 Hom.: 0

Bravo AF: 0.00170

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00302 AC: 367

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	1	Charcot-Marie-Tooth disease type 4B1 (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	MTMR2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.035
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0077	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.7	L
PhyloP100		1.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.37
Sift	Benign	0.069	T
Sift4G	Benign	0.25	T
Polyphen		0.0020	B
Vest4		0.13
MVP		0.94
MPC		0.47
ClinPred		0.024	T
GERP RS		6.2
Varity_R		0.34
gMVP		0.56
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs116750638; hg19: chr11-95568531; COSMIC: COSV105881407; COSMIC: COSV105881407;